Although the chromosomal basis of Down syndrome (DS) has been known for over 30 years, there is still a surprising lack of knowledge about causes of nondisjunction leading to trisomy 21, or to any other human trisomy. Also, little is known about risk factors that predispose DS individuals to specific birth defects. Based on our ongoing studies, we have identified important correlates to nondisjunction. We have found strong evidence that altered recombination along the nondisjoined chromosome 21 is associated with increased risk for all types of meiotic errors. New data suggest that this altered recombination may be a cell- wide phenomenon. Our preliminary analyses of environmental factors suggest that smoking and oral contraceptive use around the time of conception may predispose to one specific type of nondisjunction error, implying that risk factors affect different stages of meiosis. The success of our current studies has resulted from the combined use of cytogenetic, molecular, and epidemiological methods to study DS not as a single entity, but as subgroups defined by the type of error. We propose to extend these studies to investigate: 1) the relationship of altered recombination and maternal age; 2) individual variation in cell- wide recombination as a risk factor for nondisjunction; 3) the role of recombination in paternal nondisjunction; and 4) environmental and maternal risk factors for nondisjunction and for DS-associated birth defects. These specific aims require a substantial increase in the study population. We have a unique opportunity to ascertain over 1350 cases of trisomy 21 from well- established birth defect surveillance systems using the infrastructure established by the National Birth Defects Prevention Study. Six of the study sites (AR, CA, GA, IA, NJ, NY) will contribute a population-based sample of cases and controls. All sites are experienced in identifying, tracking, interviewing, and collecting biological samples from families with birth defects. The data resulting from this proposal will provide a valuable resource to uncover the etiology and consequences of nondisjunction of chromosome 21. These studies parallel those on other significant trisomies proposed by Dr. Terry Hassold in the companion IRPG application. Indeed, the questions and methodological approaches are nearly identical. By combining a large, population-based analysis of trisomy 21 with analyses of other autosomal and sex chromosome trisomies, we intend to characterize the genesis of the most common and clinically important human chromosome abnormalities.